Allelic Variants Of Genes Research Articles

Association of the HLA DQA1*05 allelic gene variants with immunogenicity to anti-TNF therapeutics - important differences between infliximab and adalimumab.

Association of the HLA DQA1*05 allelic gene variants with immunogenicity to anti-TNF therapeutics - important differences between infliximab and adalimumab.

Genome-wide analysis of flavonoid biosynthetic genes in Musaceae (Ensete, Musella, and Musa species) reveals amplification of flavonoid 3ʹ,5ʹ-hydroxylase

Abstract Flavonoids in Musaceae are involved in pigmentation and stress responses, including cold resistance, and are a component of the healthy human diet. Identification and analysis of the sequence and copy number of flavonoid biosynthetic genes are valuable for understanding the nature and diversity of flavonoid evolution in Musaceae species. In this study, we identified 71–80 flavonoid biosynthetic genes in chromosome-scale genome sequence assemblies of Musaceae, including those of Ensete glaucum, Musella lasiocarpa, Musa beccarii, M. acuminata, M. balbisiana and M. schizocarpa, checking annotations with BLAST and determining the presence of conserved domains. The number of genes increased through segmental duplication and tandem duplication. Orthologues of both structural and regulatory genes in the flavonoid biosynthetic pathway are highly conserved across Musaceae. The flavonoid 3ʹ,5ʹ-hydroxylase gene F3ʹ5ʹH was amplified in Musaceae and ginger compared with grasses (rice, Brachypodium, Avena longiglumis, and sorghum). One group of genes from this gene family amplified near the centromere of chromosome 2 in the x = 11 Musaceae species. Flavonoid biosynthetic genes displayed few consistent responses in the yellow and red bracts of Musella lasiocarpa when subjected to low temperatures. The expression levels of MlDFR2/3 (dihydroflavonol reductase) increased while MlLAR (leucoanthocyanidin reductase) was reduced by half. Overall, the results establish the range of diversity in both sequence and copy number of flavonoid biosynthetic genes during evolution of Musaceae. The combination of allelic variants of genes, changes in their copy numbers, and variation in transcription factors with the modulation of expression under cold treatments and between genotypes with contrasting bract-colours suggests the variation may be exploited in plant breeding programmes, particularly for improvement of stress-resistance in the banana crop.

Harnessing non-standard nucleic acids for highly sensitive icosaplex (20-plex) detection of microbial threats.

Environmental surveillance and clinical diagnostics heavily rely on the polymerase chain reaction (PCR) for target detection. A growing list of microbial threats warrants new PCR-based detection methods that are highly sensitive, specific, and multiplexable. Here, we introduce a PCR-based icosaplex (20-plex) assay for detecting 18 enteropathogen and two antimicrobial resistance genes. This multiplexed PCR assay leverages the self-avoiding molecular recognition system (SAMRS) to avoid primer dimer formation, the artificially expanded genetic information system (AEGIS) for amplification specificity, and next-generation sequencing for amplicon identification. We benchmarked this assay using a low-cost, portable sequencing platform (Oxford Nanopore) on wastewater, soil, and human stool samples. Using parallelized multi-target TaqMan Array Cards (TAC) to benchmark performance of the 20-plex assay, there was 74% agreement on positive calls and 97% agreement on negative calls. Additionally, we show how sequencing information from the 20-plex can be used to further classify allelic variants of genes and distinguish sub-species. The strategy presented offers sensitive, affordable, and robust multiplex detection that can be used to support efforts in wastewater-based epidemiology, environmental monitoring, and human/animal diagnostics.

Uncovering molecular mechanisms for amelanotic/hypopigmented primary cutaneous melanoma.

A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis. Since the degree to which somatic mutations and copy number aberrations (CNA) in genes associated with skin-lightening or albinism may contribute to the loss of tumour pigmentation in AHM samples has not yet been addressed, we have investigated loss of function mutations of key pigmentation genes in matched germline and AHM as well as pigmented melanoma (PM) tumour DNA samples. An analysis of clinical and histopathological characteristics together with whole exome sequencing data of 34 fresh frozen primary CM, graded according to the amount of pigmentation present was performed. Together with germline and somatic variant analysis, 30 samples were previously analysed for CNA changes. This study focussed on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain. The finding that red hair related MC1R and TYR R402Q loss of activity gene variant alleles and genotypes are associated with AHM was validated in this study. Germline AHM-related gene variants were enriched in 70% (n=7 of 10) of AHM patients vs 8.3% (n=2 of 24) of PM patients. This surprisingly high frequency of rare germline variants in AHM patients constitutes the "first hit" and confirms that AHM patients are more likely to be albinism allele carriers than patients with PM. Next, in CNA analysis of each tumour sample, 50% (n=4 of 8) AHM samples with a pigmentation gene variant had LOH in the region containing the corresponding gene, and 25% (=2 of 8) had loss-of-heterozygosity (LOH) in chromosomal regions of two AHM-related genes. This study proposes that the likely molecular mechanism for development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.

Epidemiology of allelic gene variants of hereditary thrombophilic condition in the population of the Arkhangelsk region

Single-nucleatide substitutions in genes encoding proteins of the hemostasis system and platelet receptors are one of the causes of hereditary predisposition to hypercoagulation and increased thrombosis. The aim is to assess the prevalence of individual allelic variants of hemostasis genes in the population of the Arkhangelsk region. Materials and methods: The study included two groups of participants from the Arkhangelsk region: patients of the Regional Center for Antithrombotic Therapy (RCATT) (n = 2354) and healthy volunteers (n = 195). The molecular genetic study of the polymorphism of the genes of the hemostasis system was carried out by PCR. The results of the study: According to the results of the study, there was no statistically significant difference in the distribution of unfavorable allelic variants of \hemostasis genes between the two groups of participants. Probably, in order to realize the hereditary tendency to increased thrombosis, it is necessary to combine the polymorphism of the studied genes with other

Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol

Introduction Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs. Protocol First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions. Discussion This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients’ genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions.

The Influence of CYP2D6 Gene Variants on Tamoxifen Therapy in Breast Cancer Patients in the Asian Region

reast cancer is one of the most prevalent cancers in society, especially among women. Tamoxifen is often used as a first-line therapy for breast cancer and reduces the risk of recurrence in ER+ breast cancer. However, the response to treatment varies due to genetic variability resulting from polymorphisms in the DNA encoding drug-metabolism enzymes, including the CYP2D6 gene. This literature review aimed to evaluate the impact of CYP2D6 gene variants on the effectiveness of tamoxifen in breast cancer treatment. A literature search was conducted through PubMed, Google Scholar, and BMC Cancer using relevant keywords. The selected articles were no more than ten years old (2014-2024), with criteria for inclusion and exclusion. The review of articles from various research journals found that in the Asian region, the CYP2D6 gene variant allele *10 was most frequently seen, resulting in Intermediate Metabolism (IM) in tamoxifen therapy. Patients with IM metabolism tend to have suboptimal therapeutic responses and require tamoxifen dose adjustments.Conversely, patients with Normal Metabolism (NM/EM) tend to have better therapeutic responses. Genetic variability in the CYP2D6 gene affects the activity of the CYP2D6 enzyme, which functions to convert tamoxifen into its active form, Endoxifen. Some individuals may have low (Poor Metabolizer), Intermediate (Intermediate Metabolizer), Normal (Extensive Metabolizer), or even high (Ultra-rapid Metabolizer) enzyme activity. Therefore, adjusting tamoxifen therapy based on patient genetic information is essential for optimal treatment, especially in Asia, where the CYP2D6 gene variant allele *10 is most commonly found, resulting in IM metabolism

Prognostic model for the development of cardiomyopathies based on genetic predictors

Aim. To develop a prognostic model for the development of primary and secondary cardiomyopathy based on genetic predictors.Material and methods. The study included 221 patients with cardiomyopathy. The mean age of the participants was 55,30±9,69 years, with the age range from 20 to 77 years. Two following groups of patients were determined: the first group (n=111) with idiopathic dilated cardiomyopathy (DCM) and the second group (n=110) with ischemic myocardial dilation. DNA was extracted from the venous blood of all participants using phenol-chloroform extraction for subsequent genotyping using polymerase chain reaction and restriction fragment length polymorphism analysis.Results. The performed multivariate analysis using the stepwise selection method showed a significant effect of the following predictors at the third step: AG/GG allelic variant of the SCN5A gene (rs1805124), 6a/6a allelic variant of the MMP3 gene (rs35068180) and the patient's age.The performed multivariate analysis using the stepwise selection showed a significant effect of the following predictors: AG/GG allelic variant of the CTLA4 gene (rs231775), AA and AG allelic variants of the SCN5A gene (rs1805124).Conclusion. Genetic studies on cardiomyopathies reveal significant associations between certain single nucleotide polymorphisms and the risk of disease development. The study results showed that the AG/GG allelic variant of the SCN5A gene (rs1805124), 6a/6a allelic variant of the MMP3 gene (rs35068180) and the patient's age have prognostic significance in the development of DCM. In addition, AG/GG allelic variant of the CTLA4 gene (rs231775), AA and AG allelic variants of the SCN5A gene (rs1805124) have prognostic significance in the development of ischemic myocardial dilation.

Living systematic review and meta-analysis of plasma-concentrations of antipsychotic drugs in carriers and non-carriers of variant CYP450 genotypes: Living systematic review protocol.

Carriers of variant alleles of genes that encode liver CYP450 and UGT enzymes may experience abnormal plasma levels of antipsychotics and, consequently, worse efficacy or tolerability. Although pharmacogenomics is a rapidly developing field, current guidelines often rely on limited, underpowered evidence. We have previously demonstrated that meta-analysis is a viable strategy for overcoming this problem. Here, we propose a project that will expand our previous work and create a living systematic review and meta-analysis of drug plasma level differences between carriers and non-carriers of variant genotype-predicted phenotypes for every pharmacokinetic drug-gene interaction relevant to commonly used antipsychotic drugs. First, a baseline systematic review and meta-analysis will be conducted by searching for observational pharmacogenomics-pharmacokinetic studies. Data on dose-adjusted drug plasma levels will be extracted, and participants will be grouped based on their genotype for each drug-gene pair separately. Differences in plasma drug levels between different phenotypes will be compared using a random-effect ratio-of-means meta-analysis. The risk of bias will be assessed using ROBINS-I, and the certainty of evidence will be assessed using GRADE. Following the establishment of baseline results, the literature search will be re-run at least once every six months, and the baseline data will be updated and re-evaluated as new evidence is published. A freely available website will be designated to present up-to-date results and conclusions. This systematic review will provide evidence-based results that are continuously updated with evidence as it emerges in the rapidly developing field of pharmacogenomics. These results may help psychiatrists in their decision-making, as clinicians are becoming increasingly aware of the patients' genetic data as testing becomes more widespread and cheaper. In addition, the results may serve as a scientific basis for the development of evidence-based pharmacogenomics algorithms for personalized dosing of antipsychotics to mitigate potentially harmful drug-gene interactions.

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

Влияние генов ADRB2 и PPARGC1A на развитие физического качества «выносливость» у единоборцев города Перми

Knowledge of genetic predisposition to certain types of sport activities will help improve the development of important physical qualities, and will also allow of scientifically based selection of the most promising athletes and adjustment of their training process. The purpose of this study is to identify the relationship between polymorphic variants of the ADRB2 (Adrenoceptor Beta 2) and PPARGC1A (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha) genes associated with endurance in athletes involved in jiu-jitsu and freestyle wrestling and schoolchildren not involved in sports. The sample for the investigation included 100 people, divided into Group I, which included martial artists, and a comparison group (Group II), which consisted of schoolchildren who did not participate sports. Studies were conducted using real-time polymerase chain reaction (RT-PCR) in subjects aged 10 to 16 years, and polymorphisms G/A of the PPARGC1A gene (rs8192678) and A/G of the ADRB2 gene (rs1042713) were identified. An analysis of the relationship between allelic variants of genes in martial artists and the comparison group was carried out. Significant differences were established between Group I and Group II for genotype G/G (Fop 3.13>1.96 at p=0.05) and genotype G/A (Fop 2.76>1.96 at p=0.05) of the PPARGC1A gene. For athletes involved in jiu-jitsu and freestyle wrestling, it has been shown that genotypes G/G and G/A of the PPARGC1A gene can be used as markers to predict the formation of the physical quality endurance. The frequency of the total genetic score (TGS) calculated for the physical quality endurance based on the polymorphism of the ADRB2 and PPARGC1A genes in 100 subjects, varied from 0 to 100. Genetic analysis data is necessary in the process of training martial artists in sports schools: based on this data, it is possible to create individual training programs taking into account the genotype and physical fitness characteristics of a particular athlete.

Genetic variants of ABCB1 and CES1 genes on dabigatran metabolism in the Kazakh population.

Allelic variants of genes encoding enzymes of the esterase system (CES1) and P-glycoprotein (ABCB1) can change the metabolism and pharmacokinetics of dabigatran. Therefore, they act as determining factors in the development of side effects, especially bleeding. We analyzed the genotype-phenotype relationship of ABCB1 (rs1045642, rs4148738, rs2032582, and rs1128503) and CES1 (rs8192935, rs71647871, and rs2244613) polymorphisms in patients with atrial fibrillation who had been treated with dabigatran. A total of 150 patients were recruited for this study. TaqMan technology was used for SNP genotyping. Patients with the rs2244613 GG genotype had a lower concentration (55.27 ± 34.22 ng/ml) compared to those with the TT genotype (63.33 ± 52.25 ng/ml) (additive model, P = 0.000). Individuals with the rs8192935 AA genotype had a lower concentration (52.72 ± 30.45 ng/ml) compared to those with the GG genotype (79.78 ± 57 ng/ml) (additive model, P = 0.001). The APTT values among the different genotypes of the ABCB1 SNPs, rs4148738 and rs1045642, were significantly different (P = 0.035 and P = 0.024, respectively). Our research demonstrates that the CES1 polymorphisms, rs8192935 and rs2244613, are associated with the pharmacodynamics and pharmacokinetics of dabigatran in the Kazakh subpopulation.

Роль генетически детерминированного дефицита лектинового пути активации комплемента при хронической инфекции Helicobacter pylori у детей

Aim. To study the association of six polymorphic regions of MBL2 (rs11003125, rs7096206, rs7095891, rs1800450, rs1800451, rs5030737), two regions of FCN2 (rs7851696, rs17549193) and one region of MASP2 (rs72550870) with Helicobacter pylori infection and the severity of neutrophilic inflammation in gastric mucosa among children with recurrent abdominal pain. Design. Genetic association study of single nucleotide polymorphisms, case — control type. Materials and methods. 96 adolescents aged 12–17 years with recurrent abdominal pain were examined. Medical history, general clinical methods and fibrogastroscopy with a biopsy of the gastric mucosa were included in the medical testing. Biopsy samples were recorded and processed to assess the neutrophil infiltration and the presence of H. pylori. The results were interpreted according to the Sydney System of Gastritis Classification. Genotyping of allelic gene variants was carried out using real-time polymerase chain reaction (MBL2, MASP2), as well as the restriction analysis of amplification products of specific genome regions (MBL2, FCN2). Results. A high rate of H. pylori colonization was associated with a high frequency of the L allele of the rs11003125 gene polymorphism of the MBL2 gene and with a decrease in the proportion of high MBL — expressing genotypes. Carriage of the Q allele of the rs7095891 gene polymorphism of the MBL2 gene was associated with less pronounced neutrophilic infiltration, and a high frequency of the T allele of the rs7851696 gene polymorphism of the FCN2 gene was associated with severe neutrophilic inflammation in gastric mucosa. No differences in the distribution of MASP2 genotypes were found. Conclusion. The results obtained suggest that genetic defects in the production of MBL and ficolin-2 may cause chronic helicobacteriosis in children and more severe inflammation of gastric mucosa. Further study of these proteins seems to be promising for new approaches to the treatment and prevention of H. pylori complications in children to be identified. Keywords: Helicobacter pylori, mannose-binding lectin, ficolin, MASP, gene polymorphism.

The neurobiology and neurocognition of gender dysphoria

Background: Gender Dysphoria (GD) is a psychological distress characterized by an incongruence between an individual's internal gender identity and the sex assigned at birth. This phenomenon has gained increased attention due to its rising prevalence, particularly among adolescents in Western societies. Objectives: This narrative literature review examines the neurocognitive, neurobiological, and neurodevelopmental aspects of GD, aiming to provide insights for the assessment of transgender adults. The growing epidemiology requires an informed and inclusive medical system. Methods: Hand searches across PubMed and Google Scholar were performed to study the neurobiological and neurocognitive aspects of Gender Dysphoria. Results: Neuroimaging studies reveal distinct brain structures in transgender women compared to cisgender men, particularly in regions like the putamen, which is involved in emotions and learning. The intricate interplay of genetic, hormonal, and neurobiological factors is implicated in GD. Differences in gray and white matter volumes, cortical thickness, and brain activation patterns have been observed in individuals with GD, implying a multifactorial basis for this condition. Neuroendocrine factors, including testosterone and estrogen levels, play a role in the development of brain structures related to sexual differentiation. Genetic contributions, such as allelic variations in genes associated with sex steroid production, have also been linked to transgenderism. The findings underscore the complexity of GD and its underlying mechanisms, contributing to a deeper understanding of this phenomenon and offering insights into assessment and support for transgender individuals.

Analysis of allelic variants in genes associated with meat productivity in regionalized small cattle breeds

The purpose of the research was to study the polymorphism of allelic variants of genes associated with high meat productivity for further selection of parental pairs using genetic methods. Genotyping of the Dagestan mountain sheep breeds (broodstock and rams) was carried out using a polymerase chain reaction. Genotyping was carried out for the following genes: CAST, GH, GDF9 on a Tertsik thermal cycler. Analysis of the results of PCR carried out with samples of sires of the Dagestan rock breed indicates that the GH gene polymorphism is represented by the A allele, with a high (0.87) and allele B, with a low (0.13) frequency of occurrence. The GDF9 gene polymorphism is represented by the GDF9G allele with a high (0.82) and the GDF9A allele with a low (0.18) frequency of occurrence. The distribution of homozygous genotype GHAA and heterozygous GHAB reached 84% and 16%, respectively. At the same time, the homozygous GHBB* genotype was absent in the studied sample. As a result of the research, new knowledge was obtained on biodiversity and forms of associations of polymorphism of the genes calpastatin, somatotropin, differential growth factor; breed-specific, population-specific features of the allelic spectrum of the CAST, GH, GDF9 genes in sheep of the Dagestan mountain sheep breed were established.

Molecular genetic markers of chemotherapy-induced cardiotoxicity in patients with oncohematological diseases (review)

Cardiotoxicity of anticancer therapy is a severe adverse cardiovascular event affecting the survival of cancer patients. Modern methods for diagnosing cardiotoxicity allow to identify already occurred myocardial transformations, accompanied by symptoms of heart failure and are not predict and detect early changes in the heart tissue during treatment. Recently, increasing attention is paid to the search for molecular genetic markers, a single identification of which before starting treatment will make possible to determining the risks of cardiotoxicity and change treatment taking into account individual genetic characteristics. At the same time, most research on the effect of allelic variants of genes on cardio-vascular complications relate to chemotherapy of solid tumors. The review considered possible prognostic genetic variants of cardiotoxicity induced by chemotherapy in patients with the hematopoietic and lymphatic malignancies.

Prognostic significance of interleukin-1a (il1a) RS1800857 genetic polymorphism in develop pulmonary sarcoidosis in residents of Karelia

The relevance of the research problem is justified by insufficient knowledge of the mechanisms for genetic regulation of inflammatory immune response during granuloma formation and arising inflammation in pulmonary sarcoidosis. It is believed that development of inflammatory process and formation of sarcoid granulomas occurs in subjects with genetically determined sensitivity to the effects of an unidentified etiological agent(s). The complexity of determining a causative factor(s) is accounted for by a variety of clinical forms and manifestations of the disease as well as a role for multifaceted immunological events in the pathogenesis of this disease. The process of inflammation, its intensity, may depend, among other issues, on host genetic background. Both enhanced and lowered production of pro-inflammatory factors can be observed in carriers of certain combinations of gene allelic variants. This, in turn, may determine human susceptibility to emergence of pulmonary sarcoidosis as well as alter clinical characteristics of the disease course and magnitude of developing immune inflammatory response. It should also be noted that the genetic background differs in various ethnic groups. Therefore, genetic background and environmental cues, ethnicity, may account for differed disease prevalence and phenotype. In this regard, it is relevant to search for allelic gene variations that could act as prognostic markers for development and progression of pulmonary sarcoidosis as well as characterize the features of its course. The data on the relationship between the carriage of allelic gene variations and susceptibility to pulmonary sarcoidosis as well as the contribution ofIL1Ars1800857 polymorphic variant to development, progression, and therapy of the disease remain sparse and often contradictory. The current study assessed a risk of lung sarcoidosis in the subjects of Russian descent of the Republic of Karelia. According to the results of the studies, a significant association (p 0.001) between the indicatedIL1Agene allelic polymorphism and pulmonary sarcoidosis was established, with a risk of its development increasing by 3.47-fold (95% CI 2.41–5.01) in carriers of the T allele (p 0.001). Thus, the single nucleotide polymorphism rs1800857 in theIL1Agene is associated with the risk of developing lung sarcoidosis in the subjects of Russian descent of the Republic of Karelia.

Aortic valve calcification is promoted by clonal hematopoiesis associated with DNMT3A and TET2 gene driver mutations

Abstract Background Clonal hematopoiesis (CH) due to DNMT3A or TET2-driver mutations is associated with coronary heart disease and worse prognosis among patients with aortic valve stenosis (AVS) and inflammation. However, it is unknown what role CH plays in the pathogenesis of AVS. AVS is the most common age-related heart valve disease, with no medical therapy to halt progression. Methods and Results Single-cell RNA-sequencing of immune cells of CAVD patients (n=13) with and without the most prevalent CH-mutations (DNMT3A and TET2), with mean CH-driver gene variant allele frequency was 6.5% for DNMT3A and 17.9% for TET2. Monocytes of patients harboring DNMT3A and TET2 mutations shared 836 upregulated genes, many associated with glycolytic, pro-inflammatory activation (CXCL10, IL38) and paracrine pro-calcific factors (oncostatin M (OSM), S100A9), suggesting that CH might be causally involved in AVS. Indeed, silencing of TET2 or DNMT3A in macrophages promotes M1-like polarization and increases release of pro-calcific mediators, particularly S100A9 and OSM. To assess whether CH-gene silenced macrophages may stimulate mesenchymal cells to secrete calcium, secreted factors from TET2 or DNMT3A-silenced macrophages were applied mesenchymal cells. Indeed, CH-gene silenced secretomes induced osteoblastic differentiation of mesenchymal cells, evidenced by increased Alizarin red calcium staining and elevated levels of ALP and RUNX2. This CH-mediated enhancement in osteoblastic conversion could be ablated by silencing of OSM. Finally, valves from atheroprone Ldlr-/- mice receiving TET2-/- bone marrow transplants demonstrated increased total calcified area (1.49-fold) along with increased numbers of calcification deposits (2.33-fold) as evidenced by von Kossa staining, along with enhanced OSM and S100A9 levels. Conclusion This is the first study to demonstrate that somatic CH-driver mutations in monocytes may accelerate AVS. Moreover, calcification was ablated via silencing of OSM in CH-gene silenced macrophages. These data suggest Oncostatin M may be a therapeutically promising target in halting the progression of AVS in patients harboring CH mutations.

Pharmacogenetics-Informed Pharmacometabolomics as an Innovative Approach to Assessing the Safety and Risk of Pharmacotherapy with Valproic Acid

Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs.Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice.Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles.Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.

5'-UTR allelic variants and expression of the lycopene-ɛ-cyclase LCYE gene in maize (Zea mays L.) inbred lines of Russian selection.

In breeding, biofortification is aimed at enriching the edible parts of the plant with micronutrients. Within the framework of this strategy, molecular screening of collections of various crops makes it possible to determine allelic variants of genes, new alleles, and the linkage of allelic variants with morphophysiological traits. The maize (Zea mays L.) is an important cereal and silage crop, as well as a source of the main precursor of vitamin A - β-carotene, a derivative of the β,β-branch of the carotenoid biosynthesis pathway. The parallel β,ε-branch is triggered by lycopene-ε-cyclase LCYE, a low expression of which leads to an increase in provitamin A content and is associated with the variability of the 5'-UTR gene regulatory sequence. In this study, we screened a collection of 165 maize inbred lines of Russian selection for 5'- UTR LCYE allelic variants, as well as searched for the dependence of LCYE expression levels on the 5'-UTR allelic variant in the leaves of 14 collection lines. 165 lines analyzed were divided into three groups carrying alleles A2 (64 lines), A5 (31) and A6 (70), respectively. Compared to A2, allele A5 contained two deletions (at positions -267- 260 and -296-290 from the ATG codon) and a G251→T substitution, while allele A6 contained one deletion (-290-296) and two SNPs (G251→T, G265→T). Analysis of LCYE expression in the leaf tissue of seedlings from accessions of 14 lines differing in allelic variants showed no associations of the 5'-UTR LCYE allele type with the level of gene expression. Four lines carrying alleles A2 (6178-1, 6709-2, 2289-3) and A5 (5677) had a significantly higher level of LCYE gene expression (~0.018-0.037) than the other 10 analyzed lines (~0.0001-0.004), among which all three allelic variants were present.